Prostate cancer is a form of cancer that develops in the prostrate, a gland in the male reproductive system. The cornerstone of treatment for men with prostate cancer (alternatively “PCa”), especially advance prostate cancer, has been androgen deprivation therapy (“ADT”), typically using a leutenizing hormone-releasing hormone (LH-RH) agonist. LH-RH is produced in the hypothalamus and induces release of luteinizing hormone (LH) from the pituitary [Schally, 2001]. As classically defined, luteininzing hormone then stimulates testosterone synthesis from Leydig cells in the male [Simoni, 1997]. ADT is typically achieved by chemical castration when luteinizing hormone-releasing hormone (LH-RH) production is suppressed at the level of the hypothalamus by LH-RH agonists.
Treatment with an LH-RH agonist can result in the palliation of painful bony metastases, decreases in the postvoid residual urine, and improved quality of life. Huggins and Hodges were awarded the Nobel Prize in 1967 for this pioneering work.
While ADT therapy is effective, the benefits are fleeting, lasting a median of 24 months. After that time, additional hormonal treatments may be attempted, but the benefit is even more transient and they are often ineffective. Unfortunately, men with castration resistant prostate cancer (“CRPC”), have few treatment options and unfortunately, often have symptomatic metastases. [Montgomery, 2008; Mostaghel, 2007].
Several studies have documented that androgen-dependent genes, like the prostate specific antigen (PSA) gene expression, are constitutively re-expressed in the absence of testicular androgens during CRPC progression [Gregory, 1998; Chen, 2004]. Progression of the castration-resistant phenotype is associated with androgen receptor amplification, mutation, responsiveness to promiscuous ligand interactions and activation of the AR signal transduction pathway through alterations in co-activators/co-repressors, and cross-talk with other signaling pathways [Feldman, 2001; Visakorpi, 1995]. However, CRPC still depends on and is enhanced by the presence of androgens.
Recently, several groups have shown that PCA cells are capable of producing testosterone directly from cholesterol [Montgomery, 2008; Dillard, 2008; Locke, 2008]. Up-regulation of genes and proteins encoding the necessary steroidogenic enzymes has been observed during CRPC progression [Locke, 2008], in metastases from patients with castration-resistant disease [Montgomery, 2008] and in an androgen-independent derivative of LNCaP cells [Dillard, 2008]. Although up-regulation of steroidogenic enzymes has been described in CRPC, the regulation of this androgen synthesis is poorly understood.
Clinical responses in patients with CRPC have been seen with the down-stream blockade of steroidogenesis in PCa cells by the CYP17 inhibitors ketoconazole and abiraterone. Ketoconazole, an antifungal with weak and non-specific CYP17 inhibitory properties, has been extensively used for the ‘off-label’ treatment of advanced CRPC. Efficacy data from phase II trials have shown that the response rate by prostate specific antigen (PSA) working group (PSAWG) criteria with ketoconazole range between 40-62% with a median duration of up to 7 months [Ang, 2009]. A trial of abiraterone acetate in chemotherapy-naïve men who had PCa that was resistant to multiple hormonal therapies demonstrated declines in PSA ≧30%, 50%, and 90% were observed in 14 (66%), 12 (57%), and 6 (29%) patients, respectively, and lasted between 69 to ≧578 days.
As such, there is a need for more effective control of androgen production in prostate cancer cells.
There is also a need for improved treatments for prostrate cancer, including castration resistant prostrate cancer.
There is also a need for new drug targets in prostate cancer, including prostate cancer cells.
The role and involvement of the Lueteninzing hormone/Luteinizing hormone receptor pathway in PCA progression is completely unexplored. The pituitary hormone LH was long thought to control steroidogenesis only in classical endocrine target cells (testicular Leydig cells) [Simoni, 1997].